The SPLIT trial: Internal vs. external validity

Introduction

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Resuscitation with large volumes of normal saline (NS) causes hyperchloremic metabolic acidosis.Some evidence suggests that hyperchloremic metabolic acidosis may impair renal function, but the clinical relevance of this remains unclear.If hyperchloremic metabolic acidosis is truly detrimental, this would be one argument to use balanced crystalloids rather than NS.

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SPLIT trial summary

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This trial randomized 2,278 patients admitted to the ICU to receive normal saline or plasmalyte.Nearly all ICU patients requiring crystalloid were included.Overall, 57% of subjects were admitted to the ICU following elective surgery, whereas 14% of subjects were admitted from the emergency department.The most common reason for admission was cardiac surgery (49%), compared to only 4% of subjects with septic shock.

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Patients in both groups received nearly the same volumes of crystalloid.The day before enrollment, patients received a median of one liter of fluid (mostly balanced crystalloids).Subsequently patients in both groups received a median of 2000 ml of study fluid over their entire ICU stay.Most of this fluid was provided on the first day:

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There were no differences in any outcome (renal failure, dialysis, serum creatinine, or mortality).

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Excellent internal validity

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This study has outstanding internal validity: it is a well-powered randomized trial with excellent enrollment and minimal bias.This trial provides strong evidence that if you work in one of the ICUs where the study was performed, it doesn't matter which crystalloid you use.If the authors of this trial decide to abandon using plasmalyte in their own practice, they would be on solid footing.

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Limited external validity

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How does this data apply to other situations?A broader interpretation of the study is that administration of 1-2 liters of normal saline would not increase the risk of renal failure compared to plasmalyte.This is not particularly controversial.Even the most ardent supporters of balanced crystalloid would probably agree that fluid selection doesn't make a big difference at a volume of 1-2 liters.The proposed mechanism of nephrotoxicity due to saline is induction of a hyperchloremic metabolic acidosis, which tends to occur with larger volumes of fluid.

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Unfortunately, this study doesn't answer the more pertinent question, which is the safety of larger volumes of saline.In the USA, a typical patient with septic shock may receive 3-4 liters of crystalloid, while a patient with severe diabetic ketoacidosis might need 4-6 liters.

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Ideally, an RCT would clarify whether hyperchloremic metabolic acidosis causes renal failure, which is the true physiologic question (figure below).This would require comparing NS with a balanced crystalloid, with administration of sufficient volumes of fluid to induce a significant hyperchloremic metabolic acidosis.Unfortunately, the SPLIT trial does not include information about whether patients receiving normal saline developed a significant hyperchloremic metabolic acidosis.Therefore, this question has not been addressed.

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The external validity of this study is also limited by the patient composition:

Patients included in this study were not very sick, with only a 9% rate of acute kidney injury and a 3% rate of dialysis. This may reflect the inclusion of patients transferred to the ICU following elective surgery. As the authors noted, these results may not apply to sicker patients.

One common cause of renal failure is sepsis-associated acute kidney injury, which has a different pathogenesis compared to other types of renal injury (Gomez 2014). Given that only 4% of the patients in this study had sepsis, it is unclear whether these results apply to sepsis resuscitation.

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Incorrect to make generalizations about all balanced crystalloids

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Studies often focus on the divide between NS and balanced crystalloids (e.g. plasmalyte and LR).However, there are also substantial differences between plasmalyte and LR:

Plasmalyte contains 23 mM of sodium gluconate, which is mostly excreted unchanged in the urine and might even act as an osmotic diuretic.

Plasmalyte contains 27 mM of sodium acetate, which the body converts into bicarbonate. Concerns have been raised about potential vasodilatory and pro-inflammatory effects of acetate (Davies 2011).

LR contains 28 mM of sodium lactate, which the body converts into bicarbonate. Although lactate has a bad reputation due to its association with shock, lactate production is often an adaptive physiologic response to stress (e.g. sodium lactate may be used as a fuel by the heart and brain).

Normal saline is occasionally referred to as “abnormal saline” due to its physiologic abnormality, but plasmalyte is also quite abnormal.There is nothing physiologic about infusing sodium gluconate and sodium acetate.Among all of these solutions, LR is arguably the most physiologic because it is a balanced crystalloid constructed from anions normally present in the blood (chloride and lactate).

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Comparison of NS vs. plasmalyte is complicated because the renal effects of gluconate and acetate are poorly understood.Therefore, a trial of NS vs. plasmalyte is simultaneously testing three unknowns: the effect of gluconate, the effect of acetate, and the effect of non-anion gap metabolic acidosis.This makes it difficult to understand the results.

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For now, LR remains my resuscitative crystalloid of choice for most patients.A better understanding of the role of LR in resuscitation would require a trial directly comparing NS vs. LR.It would not be valid to extrapolate results obtained with plasmalyte to the use of LR.

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The SPLIT trial reveals that low volumes of normal saline (e.g. two liters per entire ICU stay) produce the same renal outcomes as plasmalyte.

The SPLIT study does not reveal whether larger volumes of normal saline are equivalent to plasmalyte.

The SPLIT study does not clarify whether hyperchloremic metabolic acidosis is safe.

Differences between plasmalyte and LR make it incorrect to assume that results obtained with plasmalyte will apply to LR.

Although this study is well designed with excellent internal validity, it adds little to our understanding of large-volume resuscitation.

I think that patient population that would be best to check this in would be diabetic emergencies, such as DKA and HONK, as the protocols for these involve large volumes of NaCl over short periods of time. The problem with these patients is that often require extra potassium, which we’re not to add to LR.

Yep. I have encountered the same problem exact problem with added potassium when writing DKA protocols. I don’t believe KCl would be incompatible with LR, but most pharmacies may not let you add it.

There are two solutions to this, neither of which is perfect:
(1) Use LR-based fluids for resus and maintenance, and supplement with mini-bags of KCl
(2) Use a potassium-containing fluid (e.g. NS w/ 40 mEq/L KCl, D5 1/2 NS with 40 mEq/L KCl, etc). This may generate a hyperchloremic acidosis. In some patients with marked hyperchloremic acidosis you may end up fixing it later on with isotonic bicarbonate (D5W w/ 3 amps bicarb/liter).

For a severely acidotic patient, would avoid bolusing with NS (per solution #2).

Great assessment of the study. The low volumes received by enrolled patients and the limited number who had sepsis diagnosis really led to my essentially ignoring this study entirely and having no qualms about my LR addiction. Thanks for your thoughtful review!